This proposal describes a training program to advance my academic career in biomarker development for oncology. The purpose of this award is to encourage my transition to independent research, and this period will be used to expand my scientific knowledge and mentoring skills. During the K99 award phase, I will be mentored by Dr. Jason S. Lewis and co-mentored by Dr. Jos? Baselga and Dr. David Solit. Dr. Lewis is an Inorganic Chemist and Radiochemist with extensive experience in the preclinical validation and clinical translation of novel radiopharmaceuticals for imaging and therapy. Dr. Baselga is an internationally recognized expert in clinical oncology, devoting over 20 years to the development of therapies against the epidermal growth factor receptor (EGFR) and the closely related HER2 receptor. He was the lead investigator in the first publication that demonstrated clinical activity of the anti-HER2 monoclonal antibody trastuzumab in patients with advanced HER2 over expressing breast cancer. Dr. Solit is an expert in tyrosine kinase and steroid receptor signaling and has a substantial commitment to understanding mechanisms that lead to drug resistance. Together, Drs. Lewis, Baselga and Solit have mentored many scientists and clinical fellows, several of whom have transitioned to successful academic careers. Memorial Sloan-Kettering Cancer Center (MSKCC) will provide institutional support to me, including the resources to conduct laboratory research, opportunities to foster career development and continuing education, and an open scientific environment to foster the interaction required for me to achieve my goals. The overall goal of this project is develop companion diagnostics for monitoring treatment of pathways that lead to resistance to HER2 therapy. The proposal extends directly from my previous experience of using 89Zr trastuzumab for monitoring EGFR/HER2 therapy using afatinib. My research has established that genetic or pharmacologically driven changes in HER2 signaling pathways can be non-invasively measured with 89Zrtrastuzumab PET imaging, further underscoring a role for molecular imaging in oncology. The specific aim of this proposal during the 2-year K99 award period is to use 89Zr-trastuzumab as a non-invasive probe to evaluate the response to treatment of CD44/hyaluronan complexes that render trastuzumab-resistance in breast cancer due to steric hindrance (Specific Aim 1). With multiple adaptive defense mechanisms stimulated and induced as a consequence of therapy, the specific aim for the 3-year R00 award period (Specific Aim 2) seeks to develop immunoPET agent/s that target receptor tyrosine kinases EGFR and HER3 and demonstrate that these probes can measure pharmacologically triggered changes during targeted therapy of signaling pathways (i.e. PI3K/Akt, MEK and HER2). If proven successful, translation of this approach can ultimately provide clinicians with guidance in their decision-making to continue or re-direct cancer management to an alternative treatment regimen .